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Protein Science (2008), 17:711-724. Published by Cold Spring Harbor Laboratory Press. Copyright © 2008 The Protein Society
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Structure dissection of human progranulin identifies well-folded granulin/epithelin modules with unique functional activities

Dmitri Tolkatchev1, Suneil Malik2, Anna Vinogradova1, Ping Wang1, Zhigang Chen1, Ping Xu1, Hugh P.J. Bennett2, Andrew Bateman2, and Feng Ni1

1 Bio-NMR and Protein Research Laboratory, Biotechnology Research Institute, National Research Council of Canada, Montreal, Quebec H4P 2R2, Canada
2 Endocrine Laboratory, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec H3G 1Y6, Canada

(RECEIVED October 12, 2007; FINAL REVISION December 21, 2007; ACCEPTED December 29, 2007)

Progranulin is a secreted protein with important functions in several physiological and pathological processes, such as embryonic development, host defense, and wound repair. Autosomal dominant mutations in the progranulin gene cause frontotemporal dementia, while overexpression of progranulin promotes the invasive progression of a range of tumors, including those of the breast and the brain. Structurally, progranulin consists of seven-and-a-half tandem repeats of the granulin/epithelin module (GEM), several of which have been isolated as discrete 6-kDa GEM peptides. We have expressed all seven human GEMs using recombinant DNA in Escherichia coli. High-resolution NMR showed that only the three GEMs, hGrnA, hGrnC, and hGrnF, contain relatively well-defined three-dimensional structures in solution, while others are mainly mixtures of poorly structured disulfide isomers. The three-dimensional structures of hGrnA, hGrnC, and hGrnF contain a stable stack of two β-hairpins in their N-terminal subdomains, but showed a more flexible C-terminal subdomain. Interestingly, of the well-structured GEMs, hGrnA demonstrated potent growth inhibition of a breast cancer cell line, while hGrnF was stimulatory. Poorly folded peptides were either weakly inhibitory or without activity. The functionally active and structurally well-characterized human hGrnA offers a unique opportunity for detailed structure–function studies of these important GEM proteins as novel members of mammalian growth factors.

Keywords: granulin/epithelin module; progranulin; NMR; structure; functional activity


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